The field of the invention is combination therapies of inhibitors of γ-amino butyric acid (GABA) transaminase and Na—K—Cl cotransporter (NKCC1).
Na—K—Cl cotransporter antagonists have been proposed to treat seizures (e.g. Hochman: US2009/0258844; U.S. Pat. Nos. 7,214,711; and 6,495,601), and in particular, Bumetanide has been proposed to be useful to treat neonatal seizures (Dzhala et al. Nat. Med. 2005 November; 11(11): 1205-13), and has been reported to enhance Phenobarbital efficacy in neonatal seizure model (Dzhala et al. Ann Neurol 2008, 632:222-235)
Vigabatrin (VGB) is a known anticonvulsant that acts as an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase, the enzyme responsible for the catabolism of the inhibitory neurotransmitter GABA. The resultant increase in brain GABA levels is thought to be the mechanism of its anticonvulsant actions in infantile spasms and for refractory seizures.
Vigabatrin is associated with well documented retinal toxicity resulting in peripheral visual field deficits and also animal models that suggest intramyelinic edema in white matter areas, and in 1998 the FDA issued a “not approvable action” on vigabatrin because of its high incidence (30%) of permanent vision loss. Hence, since at least 1998 vigabatrin has been known to be effectively contraindicated for all pharmaceutical use in the United States, including use as an anticonvulsant. On Aug. 21, 2009 the FDA provided limited approval of vigabatrin for treatment seizure and infantile spasms, but required a black box warning for permanent vision loss.
We disclose that inhibitors of NKCC1 (such as bumetanide), when coadministered with inhibitors of GABA transaminase (such as vigabatrin) attenuate the retinal toxicity and/or the intramyelinic edema, and thereby expand the indications for vigabatrin and provide the first motivation for one skilled in the art to combine these two drugs for pharmaceutical delivery.
Aspects of this disclosure were published by the inventor in NIH Grant No. RC1 NS068938-01, who also has an ongoing clinical trial entitled “Pilot Study of Bumetanide for Newborn Seizures” (NCT00830531).